Last weekend at the annual meeting of the American Society of Hematology (ASH), researchers presented data on a new kind of blood thinner. Rivaroxaban (Xarelto) is a pill that works by blocking the activated form of human clotting factor X (Xa). The NEJM published the EINSTEIN* findings on-line ahead of print, coincident with the presentation.

The research includes two reported trials. In the first, an open-label randomized study of 3449 patients with acute deep venous thrombosis (DVT), subjects received either rivaroxaban pills or a standard treatment regimen starting with an injected blood thinner (enoxaparin) followed by an oral Vitamin K antagonist, like coumadin. The main findings in this Acute DVT Study was that the new drug, rivaroxaban, is as good (“non-inferior”) in terms of preventing recurrent clot as is the older regimen and bears a similar safety profile.

The second, parallel EINSTEIN-extension trial involved randomization of 1197 patients after treatment for acute DVT to take oral rivaroxaban or a placebo for an additional 6-12 month period. In this study, patients taking the experimental anticoagulant had fewer blood clots than those on placebo. Unsurprisingly, there was a slightly increased reported incidence of major bleeding (4 patients, 0.7%) in patients on the blood thinner relative to placebo (0 patients, 0%). This difference was not statistically significant.

Both trials were funded by Bayer Schering Parma and Ortho-McNeil. According to a Bayer press release of last August: “If approved by the FDA, Ortho-McNeil, a division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. (a Johnson & Johnson Company), will commercialize rivaroxaban in the U.S.”

What’s good, clearly, is that several effective anticoagulants are emerging as alternatives to heparin, which must be injected, and coumadin. In October the FDA approved the first of these drugs, dabigatran (Pradaxa), for prevention of stroke in patients with atrial fibrillation. This was big news in cardiology circles, with reason. Another area of use for these agents would be in prophylaxis for DVT in patients who undergo hip replacement and some other kinds of major surgery.

In my experience as a hematologist, and as a patient who’s had a DVT, I know that coumadin dosing is not straightforward. Because the therapeutic dose varies so much among individuals in ways that depend on genetic factors and potentially change over time with diet, patients need provide initially frequent and then periodic blood samples. The repeated blood tests don’t require large amounts of blood, but they’re annoying and costly. What’s more, the hassle – pain of blood draws, driving or walking to a clinic for sample taking, waiting for results – interferes with quality of life.

Giving intravenous blood thinners is not convenient either, as these need carefully-monitored infusion of the drug, and it’s easy to overshoot or undershoot the dose. Injectable blood thinners like low molecular weight heparin are easier to dose than conventional heparin, but still it’s pretty unpleasant for a patient to have to inject herself once or twice a day with a needle.

Soon we’ll see what the FDA says about rivaroxaban. I’m not excited about this one agent as opposed to any other, but I am enthusiastic about this new class of drugs. These should benefit people whose medical conditions warrant the use of blood thinners.

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*The “EINSTEIN” investigators are based in the Netherlands and are listed in the original paper. It’s hard to find an explanation of the acronym.

Today’s Annals of Internal Medicine includes new results for the CLOTS (Clots in Legs Or sTockings after Stroke) Trial. Not-quite acronyms aside, it’s an interesting study with implications for many patients at risk for deep venous thrombosis (DVT).

compression stockings - NIH image (Medline Plus)

This U.K.-based study, involving 3114 patients in 112 hospitals in 9 countries, used ultrasound to evaluate possible DVTs in legs of people after they’d been immobilized upon suffering strokes. Patients were randomized to receive either thigh-length or below-the-knee compression stockings while recovering in the hospital. The main result was that 98 of 1552 (6.3 %) of patients who received thigh-length stocking and 138 of 1562 (8.8%) of patients with below-the-knee stockings developed DVT. This difference is highly significant (p = 0.008).

The twist is this: in a separate, extensive recent Cochrane review the investigators compiled data from multiple randomized studies of stockings in stroke patients and established that thigh-length stockings were inferior to no stockings, i.e. stroke patients who wore thigh-high compression stockings were more likely to develop DVTs than those who didn’t wear any stockings at all. The authors reconcile these separate results by suggesting that below-knee stockings might increase the risk for DVT after stroke.

Confusing? Yes. The bottom line is that thigh-high compression stockings may not help, based on the Cochrane analysis; below-the knee stockings may hurt.

Why this matters is that the results have implications for other hospitalized patients at risk for DVT, like people who’ve had hip replacements, pelvic or spine surgery. “Unfortunately, no randomized trials have compared below-knee stockings with no stockings,” the authors write.

An accompanying editorial in the Annals considers the “puzzling” findings of the CLOTS trials and addresses how clinicians might prevent DVT in patients with stroke:

…The unexpected findings that thigh-length stockings are not very effective at preventing venous thromboembolism and that below-knee stockings might increase incidence of thrombosis in patients with stroke should prompt a reevaluation of the role of graduated compression stockings in other groups of patients….Clinicians need to realize that despite the ubiquity of graduated compression stockings in many settings, the net benefits and risks of this seemingly innocuous intervention remain uncertain.

As a hematologist, I see this as a low-tech, big deal because DVTs are a huge source of morbidity and mortality.

In the U.S., the number of clots per year runs in the hundreds of thousands. DVTs tend to arise in people who are immobilized after surgery, with neurological impairment and during travel. The elderly are particularly susceptible, as are pregnant women and people with inherited clotting dispositions. The National Blood Clot Alliance provides an interactive map of the incidence of DVTs, state by state, on its website.

Personally, I love it when the doctors allow me to take off the boots when I wake up after a procedure, so I can kick my feet around and, I hope, reduce my risk of DVT by movement and exercise. Compression stockings feel like corsets on my calves; they’re warm and constraining. On planes, too; I find stockings restrictive.

My own experience aside – the data supporting the use of compression stockings are limited, and this new study suggests they can be damaging.

A few years ago my family took a trip to China. Even before we arrived, I learned something about an unfamiliar health care culture. What I observed en route was that many of the older passengers on that long flight to Beijing were getting up from their seats and stretching. Not just once, but regularly and systematically – they were doing slow motion, isometric calisthenics on the airplane.

I took notice of their behavior first because it seemed a simple and inexpensive, albeit strange example of preventive medicine. Second, as a hematologist who cared for patients with blood clots upon traveling, I pondered the risks and benefits of their on-board exercises. Third, as a patient who’s had a blood clot, or deep venous thrombosis (DVT), I thought maybe I should follow their example.

Thrombophlebitis – the old term for DVT – happens when a vein (as opposed to an artery) gets clogged with platelets and fibrous proteins. These tend to develop in people who are immobilized – after a hip or spine surgery, for example, or during long, cramped trips in airplanes with little legroom. For this reason, long-distance travel (in any sort of vehicle – it could be a car or bus or a train) is a major risk factor.

Dehydration and some medications can exacerbate the risk of developing blood clots during travel, as can having some kinds of cancer. (Pancreatic cancer, prostate, ovarian cancer and other tumors in the pelvis are particularly troublesome in this regard.) Some people inherit an increased tendency to develop clots; in general these can be evaluated by blood tests.

Most often DVTs arise in the legs but sometimes these also occur in the arms and other body parts. The condition can cause discomfort, pain, redness and swelling of an affected limb. These clots are most dangerous, and potentially lethal, if they spread to the lung – what’s called a pulmonary embolism. So there’s good reason to avoid these as best you can.

Here’s a list of some precautions to avoid blood clots when traveling:

1. Try to get an aisle seat. This strategy allows you to periodically stretch your legs into the aisle, and to get up without disturbing others.

2. While seated, move your feet and legs around as much as circumstances permit, and at least every hour or so. If you absolutely must remain seated, flex your feet 10 times, and stretch your legs as best you can, bending and extending the knees, one at a time, in any available direction, 10 times each. Another exercise is to raise each foot and swivel it, pivoting the toes from side to side while keeping the ankle relatively still.

3. Get up periodically and walk, every hour or two if permitted. (This means getting less sleep if you’re lucky enough to fall asleep, but I think the trade-off is worth it: being tired upon arrival is unpleasant; getting a blood clot is worse than that.)

If you’re on an airplane – once you’re up and out of your seat, seek out a place near the kitchen, restroom or elsewhere where you might stand. Then, hold onto the wall or the back of a chair, lift and stretch each of your legs repeatedly and then march in place: one knee up, then the next for two minutes or so, as conditions (and flight attendants) allow.

4. Stay well-hydrated by drinking ample water. Alcohol is a diuretic and should be avoided or minimized; caffeine too. Of course, for some travelers with weak bladders drinking lots of fluids can create a need for frequent bathroom trips. But this isn’t such a bad thing if you’re at risk for DVT, because this gets you up and out of your seat.

5. Dress sensibly – avoid tight clothing. (Some doctors recommend TED (thrombo-embolic Deterrent) or other compression stockings for patients with DVTs who travel, but I find these graduated compression nylons so uncomfortable that they reduce mobility, besides the capacity to bend and flex my ankles and knees.)

For women: avoid “knee-high” stockings with compression bands pressing just below the knees. These are a set-up for reduced blood flow from the lower legs to the larger, central veins.

6. Talk to your doctor if you’re concerned about DVT and are planning a trip. Ask about what precautions you might take in the context of your specific medical circumstances. Some people use heparin, a blood-thinner, or other medications while traveling to reduce their risk. Keep in mind that for most people, the risk of forming a significant blood clot is low.